Panoply™ Human CXCR2 Over-expressing Stable Cell Line

Hormonal therapies targeting the androgen receptor (AR) were initially effective in treating prostate cancer (PCa) but ultimately failed. It has been hypothesized that the cellular heterogeneity of PCa, consisting of AR+ luminal tumor cells and AR- neuroendocrine (NE) tumor cells, may contribute to treatment failure. Here, researchers describe the successful purification of NE cells from fresh primary human prostate adenocarcinomas based on the cell surface receptor C-X-C motif chemokine receptor 2 (CXCR2). Functional studies demonstrate that CXCR2 drives the NE phenotype, including loss of AR expression, lineage plasticity, and resistance to hormonal therapy. CXCR2-driven NE cells are crucial to the tumor microenvironment because they provide a niche for AR+ luminal cells. Combining CXCR2 inhibition with AR-targeted therapy has been shown to be an effective therapeutic strategy in mouse xenograft models. This strategy has the potential to overcome therapeutic resistance caused by tumor cell heterogeneity.

To investigate whether CXCR2 drives the molecular and cellular signatures observed in NE tumor cells, the researchers overexpressed CXCR2 in LNCaP cells (LNCaP-CXCR2) and found that CXCR2-overexpressing LNCaP cells were resistant to enzalutamide (Figure 1C and D). Using GSEA analysis, they identified a gene signature in CXCR2-overexpressing LNCaP cells that was consistent with that of CXCR2+ NE cells from primary patient prostate cancer (PCa) samples. The researchers further established mouse xenograft tumors of LNCaP and LNCaP-CXCR2 and found that CXCR2 overexpression in LNCaP cells (LNCaP-CXCR2 tumors) shut down the expression of luminal markers AR and KLK3 but turned on the expression of NE marker CHGA (Figure 1E and F).

Figure 1. CXCR2-mediated phenotypic switch drives therapy resistance in PCa. (Li Y, et al., 2019)